Elucidation of NF2's tumor supressive function

描述(申请人提供)：神经纤维瘤病2型(NF2)是一种遗传性疾病，其特征是发展为第八脑神经的雪旺细胞瘤。NF2基因编码一种名为Merlin的蛋白，它与ERM蛋白(moesin、ezrin和Radisin)高度相关。Merlin被PAK磷酸化，PAK与激活的(GTP结合的)RAC/CDC42结合，作为其直接效应分子发挥作用。最近的数据表明，Merlin通过直接与PAK相互作用和抑制PAK来负向调节RAC/CDC42信号转导。这项拟议的项目旨在确定Merlin的Pak抑制功能是否也是Merlin的肿瘤抑制功能。此外，将使用细胞和动物模型来测试抑制PAK功能是否可以逆转由于NF2缺乏而产生的转化和癌症表型。最后，将进行实验以确定可能有助于NF2肿瘤抑制功能的其他机制。综上所述，这些研究将有助于更好地理解Merlin的肿瘤抑制功能。来自这些研究的PAK作为潜在的抑制靶点的确认，将直接指向开发治疗2型神经纤维瘤病的疗法的方法。

DESCRIPTION (provided by applicant): Neurofibromatosis type 2 (NF2) is an inherited disorder characterized by development of Schwann cell tumors of the eighth cranial nerve. The NF2 gene encodes a protein named merlin, which is highly related to the ERM proteins (moesin, ezrin and radixin). Merlin is phosphorylated by Paks, which bind to activated (GTP-bound) Rac/Cdc42 and function as their direct effectors. Recent data implicate that merlin negatively regulates Rac/cdc42 signaling by directly interacting with and inhibiting Paks. The proposed project is geared towards establishing whether the Pak-inhibitory function of merlin is also merlin's tumor suppressive function. Furthermore, cellular and animal models will be employed to test whether inhibiting Pak function can reverse the transformed and cancer phenotypes that arise from NF2 deficiency. Finally, experiments will be carried out to identify additional mechanisms that may contribute to NF2 tumor suppressor function. Taken together, these studies will lead to a better understanding of merlin's tumor suppressive function. The validation of Paks as potential targets for inhibition, stemming from these studies, will point directly at approaches for the development of therapeutics towards the treatment of neurofibromatosis type 2.